Indole Amide Derivatives as Ep4 Receptot Ligands

ABSTRACT

The invention is directed to indoline amide derivatives as EP4 receptor ligands, antagonists or agonists, useful for the treatment of EP4 mediated diseases or conditions, such as acute and chronic pain, osteoarthritis, rheumatoid arthritis, cancer and glaucoma. Pharmaceutical compositions and methods of use are also included.

BACKGROUND OF THE INVENTION

This invention relates to compounds and methods for treatingprostaglandin E mediated diseases, and certain pharmaceuticalcompositions thereof. The present invention is directed to novelcompounds that are ligands, antagonists or agonists, of the EP4 subtypeof PGE₂ receptors. Compounds of the invention that are antagonists ofthe pain and inflammatory effects of E-type prostaglandins arestructurally different from NSAIDs and opiates.

Three review articles describe the characterization and therapeuticrelevance of the prostanoid receptors as well as the most commonly usedselective agonists and antagonists: Eicosanoids: From Biotechnology toTherapeutic Applications, Folco, Samuelsson, Maclouf, and Velo eds,Plenum Press, New York, 1996, chap. 14, 137-154; Journal of LipidMediators and Cell Signalling, 1996, 14, 83-87; and Prostaglandins andOther Lipid Mediators, 2002, 69, 557-573.

Thus, selective prostaglandin ligands, agonists or antagonists,depending on which prostaglandin E receptor subtype is being considered,have anti-inflammatory, antipyretic and analgesic properties similar toa conventional non-steroidal anti-inflammatory drug, and in addition,have effects on vascular homeostasis, reproduction, gastrointestinalfunctions and bone metabolism. These compounds may have a diminishedability to induce some of the mechanism-based side effects of NSAIDswhich are indiscriminate cyclooxygenase inhibitors. In particular, thecompounds are believed to have a reduced potential for gastrointestinaltoxicity, a reduced potential for renal side effects, a reduced effecton bleeding times and a lessened ability to induce asthma attacks inaspirin-sensitive asthmatic subjects.

In The Journal of Clinical Investigation (2002, 110, 651-658), studiessuggest that chronic inflammation induced by collagen antibody injectionin mice is mediated primarily through the EP4 subtype of PGE₂ receptors.Patent application publications WO 96/06822 (Mar. 7, 1996), WO 96/11902(Apr. 25, 1996) and EP 752421-A1 (Jan. 8, 1997) disclose compounds asbeing useful in the treatment of prostaglandin mediated diseases.

The present invention is directed to novel compounds that are ligands,antagonists or agonists, of the EP4 subtype of PGE₂ receptors. Thecompounds would therefore be useful for the treatment of diseases orconditions mediated by the EP4 receptor, such as acute and chronic pain,osteoarthritis, rheumatoid arthritis, cancer and glaucoma.

SUMMARY OF THE INVENTION

The invention is directed to indoline amide derivatives as EP4 receptorligands, antagonists or agonists, useful for the treatment of EP4mediated diseases or conditions, such as acute and chronic pain,osteoarthritis, rheumatoid arthritis, cancer and glaucoma.Pharmaceutical compositions and methods of use are also included.

DETAILED DESCRIPTION OF THE INVENTION

The invention encompasses a genus of compounds of Formula I

or a pharmaceutically acceptable salt thereof, wherein:X is —COOH or tetrazol-5-yl;each of A, B and C is independently selected from N, CH and C(R³), withthe proviso that not more than one of A, B or C may be N;D is —C(R)₂— or —N(R)—, wherein each R is independently selected fromthe group consisting of: hydrogen, C₁₋₄alkyl, C₁₋₄-fluoroalkyl,C₁₋₄alkoxy, C₁₋₄-fluoroalkoxy and acetyl;Ar¹ and Ar² are independently selected from the group consisting of:C₃₋₆cycloalkyl, aryl, heteroaryl and heterocyclyl, or a fused analog ofC₃₋₆cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein Ar¹ isoptionally substituted with one to three R¹ groups and Ar² is optionallysubstituted with one to three R² groups; andeach R¹, R² and R³ is independently selected from the group consistingof: halo, —CN, C₁₋₄alkyl, C₁₋₄-fluoroalkyl, C₁₋₄alkoxy,C₁₋₄fluoroalkoxy, acetyl, aminocarbonyl and phenyl, R⁴ and R⁵ areselected from the group consisting: hydrogen and C₁₋₄alkyl, or R⁴ and R⁵may be joined together with the atom to which they are attached to forma C₃₋₆cycloalkyl group.

Within the genus, the invention encompasses a sub-genus of compounds ofFormula I wherein R⁴ is methyl and R⁵ is hydrogen or R⁴ and R⁵ arejoined together with the atom to which they are attached to formcyclopropyl.

Also within the genus, the invention encompasses a sub-genus ofcompounds of Formula I wherein Ar¹ is phenyl, optionally substitutedwith one to three R¹ groups.

Also within the genus, the invention encompasses a sub-genus ofcompounds of Formula I wherein Ar² is phenyl, optionally substitutedwith one to three R² groups.

Also within the genus, the invention encompasses a sub-genus ofcompounds of Formula I wherein each of A, B and C is independentlyselected from CH and C(R³).

Also within the genus, the invention encompasses a sub-genus ofcompounds of Formula I wherein X is —COOH.

Also within the genus, the invention encompasses a sub-genus ofcompounds of Formula Ia

or a pharmaceutically acceptable salt thereof, wherein:R² is selected from the group consisting of: halo, —CN, C₁₋₄alkyl,C₁₋₄fluoroalkyl, C₁₋₄alkoxy, C₁₋₄fluoroalkoxy, acetyl, aminocarbonyl andphenyl.

Within this sub-genus, the invention encompasses a class of compounds ofFormula Ia wherein at least one R² group is present.

The invention also encompasses a compound selected from the followinggroup:

-   4-[(1S)-1-({[1-(3-chlorobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({[1-(3-chlorobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-{(1S)-1-[({1-[4-(trifluoromethoxy)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic    acid;-   4-[(1S)-1-({[1-(3-cyanobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({[1-(4-cyanobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({[1-(3-chloro-4-iodobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({[1-(4-iodobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({[1-(3,5-dibromobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-{(1S)-1-[({1-[3-(aminocarbonyl)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic    acid;-   4-[(1S)-1-({[1-(3,4-dichlorobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-{(1S)-1-[({1-[3-(trifluoromethyl)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic    acid;-   4-[(1S)-1-({[1-(biphenyl-4-ylmethyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({[1-(4-bromobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-{(1S)-1-[({1-[4-(aminocarbonyl)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic    acid;-   4-{(1S)-1-[({1-[4-(trifluoromethyl)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic    acid;-   4-[(1S)-1-({[1-(2,5-dichlorobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[1-({[1-(3,4-dichlorobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)cyclopropyl]benzoic    acid;-   4-[(1S)-1-({[1-(2-naphthylmethyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic    acid;-   1-(3,4-dichlorobenzyl)-N-{1-[4-(1H-tetrazol-5-yl)phenyl]cyclopropyl}indoline-7-carboxamide;-   4-{(1S)-1-[({1-[2-bromo-4-(trifluoromethyl)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic    acid;-   4-{(1S)-1-[({1-[4-(chloro)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic    acid;-   N-{(1S)-1-[4-(1H-tetrazol-5-yl)phenyl]ethyl-1-[4-(trifluoromethyl)benzyl]indoline-7-carboxamide;    and-   4-{(1S)-1-[({5-chloro-1-[4-(chloro)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic    acid;    or a pharmaceutically acceptable salt of any of the aforementioned.

The invention also encompasses a pharmaceutical composition comprising acompound of Formula I in admixture with one or more physiologicallyacceptable carriers or excipients.

The invention also encompasses a compound of Formula I or apharmaceutically acceptable derivative thereof for use in human orveterinary medicine.

The invention also encompasses a method of treating a human or animalsubject suffering from a condition which is mediated by the action ofPGE2 at EP4 receptors, which method comprises administering to saidsubject an effective amount of a compound of Formula I.

The invention also encompasses the use of a compound of Formula I forthe manufacture of a therapeutic agent for the treatment of a conditionwhich is mediated by the action of PGE2 at EP4 receptors.

DEFINITIONS

“Alkyl”, as well as other groups having the prefix “alk”, such asalkoxy, alkanoyl, means carbon chains which may be linear or branched orcombinations thereof. Examples of alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl,octyl, nonyl, and the like.

“Fluoroalkyl” means alkyl as defined above wherein one or more hydrogenatoms have been replaced by fluoro atoms.

“Alkenyl” means carbon chains which contain at least one carbon-carbondouble bond, and which may be linear or branched or combinationsthereof. Examples of alkenyl include vinyl, allyl, isopropenyl,pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl,and the like.

“Alkynyl” means carbon chains which contain at least one carbon-carbontriple bond, and which may be linear or branched or combinationsthereof. Examples of alkynyl include ethynyl, propargyl,3-methyl-1-pentynyl, 2-heptynyl and the like.

“Cycloalkyl” means mono- or bicyclic saturated carbocyclic rings, eachof which having from 3 to 10 carbon atoms. A “fused analog” ofcycloalkyl means a monocyclic rings fused to an aryl or heteroaryl groupin which the point of attachment is on the non-aromatic portion.Examples of cycloalkyl and fused analogs thereof include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl,decahydronaphthyl, indanyl, and the like.

“Alkoxy” means alkoxy groups of a straight or branched having theindicated number of carbon atoms. C₁₋₆alkoxy, for example, includesmethoxy, ethoxy, propoxy, isopropoxy, and the like.

“Cycloalkoxy” means cycloalkyl as defined above bonded to an oxygenatom, such as cyclopropyloxy.

“Fluoroalkoxy” means alkoxy as defined above wherein one or morehydrogen atoms have been replaced by fluoro atoms.

“Aryl” means mono- or bicyclic aromatic rings containing only carbonatoms. A “fused analog” of aryl means an aryl group fused to amonocyclic cycloalkyl or monocyclic heterocyclyl group in which thepoint of attachment is on the aromatic portion. Examples of aryl andfused analogs thereof include phenyl, naphthyl, indanyl, indenyl,tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydrobenzopyranyl,1,4-benzodioxanyl, and the like.

“Heteroaryl” means a mono- or bicyclic aromatic ring containing at leastone heteroatom selected from N, O and S, with each ring containing 5 to6 atoms. A “fused analog” of heteroaryl means a heteroaryl group fusedto a monocyclic cycloalkyl or monocyclic heterocyclyl group in which thepoint of attachment is on the aromatic portion. Examples of heteroarylinclude pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl,oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl,pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl,benzothiophenyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, andthe like.

“Heterocyclyl” means mono- or bicyclic saturated rings containing atleast one heteroatom selected from N, S and O, each of said ring havingfrom 3 to 10 atoms in which the point of attachment may be carbon ornitrogen. A “fused analog” of heterocyclyl means a monocyclicheterocycle fused to an aryl or heteroaryl group in which the point ofattachment is on the non-aromatic portion. Examples of “heterocyclyl”and fused analogs thereof include pyrrolidinyl, piperidinyl,piperazinyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl,benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl,dihydroindolyl, and the like. The term also includes partiallyunsaturated monocyclic rings that are not aromatic, such as 2- or4-pyridones attached through the nitrogen orN-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils).

“Halogen” and “halo” includes fluorine, chlorine, bromine and iodine.

Optical Isomers—Diastereomers—Geometric Isomers—Tautomers

Compounds of Formula I contain one or more asymmetric centers and canthus occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. The presentinvention is meant to comprehend all such isomeric forms of thecompounds of Formula I.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist with different pointsof attachment of hydrogen, referred to as tautomers. Such an example maybe a ketone and its enol form known as keto-enol tautomers. Theindividual tautomers as well as mixture thereof are encompassed withcompounds of Formula I.

Compounds of the Formula I may be separated into diastereoisomeric pairsof enantiomers by, for example, fractional crystallization from asuitable solvent, for example MeOH or EtOAc or a mixture thereof. Thepair of enantiomers thus obtained may be separated into individualstereoisomers by conventional means, for example by the use of anoptically active amine as a resolving agent or on a chiral HPLC column.

Alternatively, any enantiomer of a compound of the general Formula I maybe obtained by stereospecific synthesis using optically pure startingmaterials or reagents of known configuration.

Salts

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, magnesium, potassium, and sodium salts. Salts derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethyl-aminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,histidine, hydrabamine, isopropylamine, lysine, methyl-glucamine,morpholine, piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particularly preferred are citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, and tartaric acids.

It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Utilities

Compounds of the invention are ligands of the EP4 receptor and thus areuseful as antagonists or agonists of the EP4 receptor and have utilityfor treating diseases or condition mediated by this receptor.

In view of their ability to bind to the EP4 receptor, the compounds ofthe invention are useful in the treatment of one or more of thedisorders that follow, depending on whether the compound is anantagonist or an agonist.

Compounds of the invention which are antagonists of the EP4 subtype ofPGE₂ receptors are useful for treating diseases or conditions such asacute and chronic pain, osteoarthritis, rheumatoid arthritis and cancer.

Compounds of the invention are useful as analgesics. For example theyare useful in the treatment of chronic articular pain (e.g. rheumatoidarthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis andjuvenile arthritis) including the property of disease modification andjoint strucure preservation; musculoskeletal pain; lower back and neckpain; sprains and strains; neuropathic pain; sympathetically maintainedpain; myositis; pain associated with cancer and fibromyalgia; painassociated with migraine; pain associated with influenza or other viralinfections, such as the common cold; rheumatic fever; pain associatedwith functional bowel disorders such as non-ulcer dyspepsia, non-cardiacchest pain and irritable bowel syndrome; pain associated with myocardialischemia; post operative pain; headache; toothache; and dysmenorrhea.

Compounds of the invention are useful in the treatment of neuropathicpain. Neuropathic pain syndromes can develop following neuronal injuryand the resulting pain may persist for months or years, even after theoriginal injury has healed. Neuronal injury may occur in the peripheralnerves, dorsal roots, spinal cord or certain regions in the brain.Neuropathic pain syndromes are traditionally classified according to thedisease or event that 25 precipitated them. Neuropathic pain syndromesinclude: diabetic neuropathy; sciatica; non-specific lower back pain;multiple sclerosis pain; fibromyalgia; HIV related neuropathy;post-herpetic neuralgia; trigeminal neuralgia; and pain resulting fromphysical trauma, amputation, cancer, toxins or chronic inflammatoryconditions. These conditions are difficult to treat and although severaldrugs are known to have limited efficacy, complete pain control israrely achieved. The symptoms of neuropathic pain are incrediblyheterogeneous and are often described as spontaneous shooting andlancinating pain, or ongoing, burning pain. In addition, there is painassociated with normally non-painful sensations such as “pins andneedles” (paraesthesias and dysesthesias), 35 increased sensitivity totouch (hyperesthes;a), painful sensation following innocuous stimulation(dynamic, static or thermal allodynia), increased sensitivity to noxiousstimuli (thermal, cold, mechanical hyperalgesia), continuing painsensation after removal of the stimulation (hyperpathia) or an absenceof or deficit in selective sensory pathways (hypoalgesia).

Compounds of the invention are also useful in the treatment ofinflammation, for example in the treatment of skin conditions (e.g.sunburn, burns, eczema, dermatitis, psoriasis); ophthalmic diseases suchas glaucoma, retinitis, retinopathies, uveitis and of acute injury tothe eye tissue (e.g. conjunctivitis); lung disorders (e.g. asthma,bronchitis, emphysema, allergic rhinitis, respiratory distress syndromepigeon fancier's disease, farmer's lung, CORD); gastrointestinal tractdisorders (e.g. aphthous ulcer, Crohn's disease, atopic gastritis,gastritis varialoforme, ulcerative colitis, coeliac disease, regionalileitis, irritable bowel syndrome, inflammatory bowel disease,gastrointestinal reflux disease); organ transplantation; otherconditions with an inflammatory component such as vascular disease,migraine, periarteritis nodosa, thyroiditis, aplastic anaemia, Hodgkin'sdisease, sclerodoma, myaesthenia gravis, multiple sclerosis,sorcoidosis, nephrotic syndrome, Bechet's syndrome, polymyositis,gingivitis, myocardial ischemia, pyrexia, systemic lupus erythematosus,polymyositis, tendinitis, bursitis, and Sjogren's syndrome.

Compounds of the invention are also useful in the treatment ofimmunological diseases such as autoimmune diseases, immunologicaldeficiency diseases or organ transplantation. The compounds of theinvention are also effective in increasing the latency of HIV infection.

Compounds of the invention are also useful in the treatment of diseasesof abnormal platelet function (e.g. occlusive vascular diseases).

Compounds of the invention are also useful for the preparation of a drugwith diuretic action.

Compounds of the invention are also useful in the treatment of impotenceor erectile dysfunction.

Compounds of the invention are also useful in the treatment of bonedisease characterized by abnormal bone metabolism or resorption such asosteoporosis (especially postmenopausal osteoporosis), hyper-calcemia,hyperparathyroidism, Paget's bone diseases, osteolysis, hypercalcemia ofmalignancy with or without bone metastases, rheumatoid arthritis,periodontitis, osteoarthritis, ostealgia, osteopenia, cancer cacchexia,calculosis, lithiasis (especially urolithiasis), solid carcinoma, goutand ankylosing spondylitis, tendinitis and bursitis. In a further aspectcompounds of the invention may be useful in inhibiting bone resorptionand/or promoting bone generation.

Compounds of the invention are also useful for attenuating thehemodynamic side effects of NSAIDs and COX-2 inhibitors.

Compounds of the invention are also useful in the treatment ofcardiovascular diseases such as hypertension or myocardiac ischemia;functional or organic venous insufficiency; varicose therapy;haemorrhoids; and shock states associated with a marked drop in arterialpressure (e.g. septic shock).

Compounds of the invention are also useful in the treatment ofneurodegenerative diseases and neurodegeneration such as dementia,particularly degenerative dementia (including senile dementia,Alzheimer's disease, Pick's disease, Huntingdon's chores, Parkinson'sdisease and Creutzfeldt-Jakob disease, ALS, motor neuron disease);vascular dementia (including multi-infarct dementia); as well asdementia associated with intracranial space occupying lesions; trauma;infections and related conditions (including HIV infection); metabolism;toxins; anoxia and vitamin deficiency; and mild cognitive impairmentassociated with ageing, particularly Age Associated Memory Impairment.

The compounds of Formula I are also useful in the treatment ofneuroprotection and in the treatment of neurodegeneration followingstroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinalcord injury or the like. Compounds of the invention are also useful forthe treatment of stroke and multiple sclerosis.

Compounds of the invention are also useful in the treatment of tinnitus.

Compounds of the invention are also useful in preventing or reducingdependence on, or preventing or reducing tolerance or reverse toleranceto, a dependence—inducing agent. Examples of dependence inducing agentsinclude opioids (e.g. morphine), CNS depressants (e.g. ethanol),psychostimulants (e.g. cocaine) and nicotine.

Compounds of the invention are also useful in the treatment ofcomplications of Type 1 diabetes (e.g. diabetic microangiopathy,diabetic retinopathy, diabetic nephropathy, macular degeneration,glaucoma), nephrotic syndrome, aplastic anaemia, uveitis, Kawasakidisease and sarcoidosis.

Compounds of the invention are also useful in the treatment of kidneydysfunction (nephritis, particularly mesangial proliferativeglomerulonephritis, nephritic syndrome), liver dysfunction (hepatitis,cirrhosis), gastrointestinal dysfunction (diarrhoea) and colon cancer.

Compounds of the invention are also useful for treating or preventing aneoplasia in a subject in need of such treatment or prevention. The term“treatment” includes partial or total inhibition of the neoplasiagrowth, spreading or metastasis, as well as partial or total destructionof the neoplastic cells and/or symptoms associated with neoplasiaincluding pain, anorexia or weight loss. The term also includes the useof compounds as sensitizing agents for other chemotherapies. The term“prevention” includes either preventing the onset of clinically evidentneoplasia altogether or preventing the onset of a preclinically evidentstage of neoplasia in individuals at risk. Also intended to beencompassed by this definition is the prevention of initiation formalignant cells or to arrest or reverse the progression of premalignantcells to malignant cells. This includes prophylactic treatment of thoseat risk of developing the neoplasia. The term “subject” for purposes oftreatment includes any human or mammal subject who has any one of theknown neoplasias, and preferably is a human subject. For methods ofprevention, the subject is any human or animal subject, and preferablyis a human subject who is at risk for obtaining a neoplasia. The subjectmay be at risk due to exposure to carcinogenic agents, being geneticallypredisposed to have the neoplasia, and the like.

The term “neoplasia” includes both benign and cancerous tumors, growthsand polyps. Thus, the compounds of the invention are useful for treatingor preventing benign tumors, growths and polyps including squamous cellpapilloma, basal cell tumor, transitional cell papilloma, adenoma,gastrinoma, cholangiocellular adenoma, hepatocellular adenoma, renaltubular adenoma, oncocytoma, glomus tumor, melanocytic nevus, fibroma,myxoma, lipoma, leiomyoma, rhabdomyoma, benign teratoma, hemangioma,osteoma, chondroma and meningioma. The compounds of the invention arealso useful for treating or preventing cancerous tumors, growths andpolyps including squamous cell carcinoma, basal cell carcinoma,transitional cell carcinoma, adenocarcinoma, malignant gastrinoma,cholangiocelleular carcinoma, hepatocellular carcinoma, renal cellcarcinoma, malignant melanoma, fibrosarcoma, myxosarcoma, liposarcoma,leimyosarcoma, rhabdomyosarcoma, malignant teratoma, hemangiosarcoma,Kaposi sarcoma, lymphangiosarcoma, ostreosarcoma, chondrosarcoma,malignant meningioma, non-Hodgkin lymphoma, Hodgkin lymphoma andleukemia. For purposes of this specification, “neoplasia” includes braincancer, bone cancer, epithelial cell-derived neoplasia (epithelialcarcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinalcancer such as lip cancer, mouth cancer, esophogeal cancer, small bowelcancer and stomach cancer, colon cancer, rectal cancer, liver cancer,bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lungcancer, breast cancer and skin cancer, such as squamus cell and basalcell cancers, prostate cancer, renal cell carcinoma, and other knowncancers that affect epithelial, mesenchymal or blood cells throughoutthe body. The compounds of the invention are useful for treating orpreventing any of the aforementioned cancers. The compounds of theinvention are useful for treating or preventing benign and canceroustumors, growths and polyps of the following cell types: squamousepithelium, basal cells, transitional epithelium, glandular epithelium,G cells, bile ducts epithelium, hepatocytes, tubules epithelium,melanocytes, fibrous connective tissue, cardiac skeleton, adiposetissue, smooth muscle, skeletal muscle, germ cells, blood vessels,lymphatic vessels, bone, cartilage, meninges, lymphoid cells andhematopoietic cells. The compounds can be used to treat subjects havingadenomatous polyps, including those with familial adenomatous polyposis(FAP). Additionally, the compounds can be used to prevent polyps fromforming in patients at risk of FAP. Preferably, the compounds of theinvention are useful for treating or preventing the following cancers:colorectal, esophagus stomach, breast, head and neck, skin, lung, liver,gall bladder, pancreas, bladder, endometrium cervix, prostate, thyroidand brain.

It is to be understood that reference to treatment includes bothtreatment of established symptoms and prophylactic treatment, unlessexplicitly stated otherwise.

EP4 agonists of the present invention are useful for treating ocularhypertension, glaucoma, macular edema, macular degeneration, forincreasing retinal and optic nerve head blood velocity, for increasingretinal and optic nerve oxygen tension, for providing a neuroprotectiveeffect or for a combination thereof. EP4 agonists of the presentinvention are also useful for treating disease states or conditionsrelated to abnormal bone resorption including, but are not limited to,osteoporosis, glucocorticoid induced osteoporosis, Paget's disease,abnormally increased bone turnover, periodontal disease, tooth loss,bone fractures, rheumatoid arthritis, periprosthetic osteolysis,osteogenesis imperfecta, metastatic bone disease, hypercalcemia ofmalignancy, and multiple myeloma.

Dose Ranges

The magnitude of prophylactic or therapeutic dose of a compound ofFormula I will, of course, vary with the nature and severity of thecondition to be treated, and with the particular compound of Formula Iused and its route of administration. The dose will also vary accordingto the age, weight and response of the individual patient. In general,the daily dose range lie within the range of from about 0.001 mg toabout 100 mg per kg body weight of a mammal, preferably 0.01 mg to about50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single ordivided doses. On the other hand, it may be necessary to use dosagesoutside these limits in some cases.

For use where a composition for intravenous administration is employed,a suitable dosage range is from about 0.01 mg to about 25 mg (preferablyfrom 0.1 mg to about 10 mg) of a compound of Formula I per kg of bodyweight per day.

In the case where an oral composition is employed, a suitable dosagerange is, e.g. from about 0.01 mg to about 100 mg of a compound ofFormulas I or I a per kg of body weight per day, preferably from about0.1 mg to about 10 mg per kg.

For use where a composition for sublingual administration is employed, asuitable dosage range is from 0.01 mg to about 25 mg (preferably from0.1 mg to about 5 mg) of a compound of Formula I per kg of body weightper day.

Pharmaceutical Compositions

Another aspect of the present invention provides pharmaceuticalcompositions which comprises a compound of Formula I and apharmaceutically acceptable carrier. The term “composition”, as inpharmaceutical composition, is intended to encompass a productcomprising the active ingredient(s), and the inert ingredient(s)(pharmaceutically acceptable excipients) that make up the carrier, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing a compound ofFormula I, additional active ingredient(s), and pharmaceuticallyacceptable excipients.

Any suitable route of administration may be employed for providing amammal, especially a human with an effective dosage of a compound of thepresent invention. For example, oral, sublingual, rectal, topical,parenteral, ocular, pulmonary, nasal, and the like may be employed.Dosage forms include tablets, troches, dispersions, suspensions,solutions, capsules, creams, ointments, aerosols, and the like.

The pharmaceutical compositions of the present invention comprise acompound of Formula I as an active ingredient or a pharmaceuticallyacceptable salt thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. Theterm “pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic bases or acids including inorganicbases or acids and organic bases or acids.

The compositions include compositions suitable for oral, sublingual,rectal, topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (aerosol inhalation), ornasal administration, although the most suitable route in any given casewill depend on the nature and severity of the conditions being treatedand on the nature of the active ingredient. They may be convenientlypresented in unit dosage form and prepared by any of the methodswell-known in the art of pharmacy.

For administration by inhalation, the compounds of the present inventionare conveniently delivered in the form of an aerosol spray presentationfrom pressurized packs or nebulizers. The compounds may also bedelivered as powders which may be formulated and the powder compositionmay be inhaled with the aid of an insufflation powder inhaler device.The preferred delivery systems for inhalation are metered doseinhalation (MDI) aerosol, which may be formulated as a suspension orsolution of a compound of Formula I in suitable propellants, such asfluorocarbons or hydrocarbons and dry powder inhalation (DPI) aerosol,which may be formulated as a dry powder of a compound of Formula I withor without additional excipients.

Suitable topical formulations of a compound of formula I includetransdermal devices, aerosols, creams, ointments, lotions, dustingpowders, and the like.

In practical use, the compounds of Formula I can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, capsules and tablets, with the solid oral preparationsbeing preferred over the liquid preparations. Because of their ease ofadministration, tablets and capsules represent the most advantageousoral dosage unit form in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be coated by standardaqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compounds ofFormula I may also be administered by controlled release means and/ordelivery devices such as those described in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient, as a powder or granules or as a solution or a suspension inan aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or awater-in-oil liquid emulsion. Such compositions may be prepared by anyof the methods of pharmacy but all methods include the step of bringinginto association the active ingredient with the carrier whichconstitutes one or more necessary ingredients. In general, thecompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into the desiredpresentation. For example, a tablet may be prepared by compression ormolding, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing in a suitable machine, the activeingredient in a free-flowing form such as powder or granules, optionallymixed with a binder, lubricant, inert diluent, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent. Desirably, each tablet contains from about 1 mg to about500 mg of the active ingredient and each cachet or capsule contains fromabout 1 to about 500 mg of the active ingredient.

Combination Therapy

Compounds of Formula I may be used in combination with other drugs thatare used in the treatment/prevention/suppression or amelioration of thediseases or conditions for which compounds of Formula I are useful. Suchother drugs may be administered, by a route and in an amount commonlyused therefor, contemporaneously or sequentially with a compound ofFormula I. When a compound of Formula I is used contemporaneously withone or more other drugs, a pharmaceutical composition containing suchother drugs in addition to the compound of Formula I is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients, inaddition to a compound of Formula I. Examples of other activeingredients that may be combined with a compound of Formula I, eitheradministered separately or in the same pharmaceutical compositions,include, but are not limited to: COX-2 inhibitors, such as celecoxib,rofecoxib, etoricoxib, valdecoxib or parecoxib; 5-lipoxygenaseinhibitors; NSAIDs, such as diclofenac, indomethacin, nabumetone oribuprofen; leukotriene receptor antagonists; DMARDs such asmethotrexate; adenosine A1 receptor agonists; sodium channel blockers,such as lamotrigine; NMDA receptor modulators, such as glycine receptorantagonists; gabapentin and related compounds; tricyclic antidepressantssuch as amitriptyline; neurone stabilising antiepileptic drugs;mono-aminergic uptake inhibitors such as venlafaxine; opioid analgesics;local anaesthetics; 5HT agonists, such as triptans, for examplesumatriptan, naratriptan, zolmitriptan, eletriptan, frovatriptan,almotriptan or rizatriptan; EP1 receptor ligands; EP2 receptor ligands;EP3 receptor ligands; EP1 antagonists; EP2 antagonists and EP3antagonists. When the compounds are used in combination with othertherapeutic agents, the compounds may be administered eithersequentially or simultaneously by any convenient route.

The invention thus provides, in a further aspect, a combinationcomprising a compound of Formula I or a pharmaceutically acceptablederivative thereof together with a further therapeutic agent or agents.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with apharmaceutically acceptable carrier or excipient comprise a furtheraspect of the invention. The individual components of such combinationsmay be administered either sequentially or simultaneously in separate orcombined pharmaceutical formulations.

The weight ratio of the compound of the Formula I to the second activeingredient may be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used. Thus, forexample, when a compound of Formula I is combined with an NSAID theweight ratio of the compound of Formula I to the NSAID will generallyrange from about 1000:1 to about 1:1000, preferably about 200:1 to about1:200. Combinations of a compound of Formula I and other activeingredients will generally also be within the aforementioned range, butin each case, an effective dose of each active ingredient should beused.

Assays for Determining Biological Activity

The compounds of Formula I can be tested using the following assays todetermine their prostanoid antagonist or agonist activity in vitro andin vivo and their selectivity. The prostaglandin receptor activitiesdemonstrated are DP, EP₁, EP₂, EP₃, EP₄, FP, IP and TP.

Stable Expression of Prostanoid Receptors in the Human Embryonic Kidney(HEK) 293(ebna) Cell Line

Prostanoid receptor cDNAs corresponding to full length coding sequencesare subcloned into the appropriate sites of mammalian expression vectorsand transfected into HEK 293(ebna) cells. HEK 293(ebna) cells expressingthe individual cDNAs are grown under selection and individual coloniesare isolated after 2-3 weeks of growth using the cloning ring method andsubsequently expanded into clonal cell lines.

Prostanoid Receptor Binding Assays

Transfected HEK 293(ebna) cells are maintained in culture, harvested andmembranes are prepared by differential centrifugation, following lysisof the cells in the presence of protease inhibitors, for use in receptorbinding assays. Prostanoid receptor binding assays (for DP1, DP2(CRTH2), EP1, EP2, EP3-III, EP4, FP, IP, and TP) are performed in 10 mMMES/KOH (pH 6.0) (EPs, FP and TP) or 10 mM HEPES/KOH (pH 7.4) (DPs andIP), containing 1 mM EDTA, 2.5-30 mM divalent cation and the appropriateradioligand. Synthetic compounds are added in dimethylsulfoxide which iskept constant at 1% (v/v) in all incubations. The reaction is initiatedby addition of membrane protein. Non-specific binding is determined inthe presence of 10 μM of the corresponding non-radioactive prostanoid.Incubations are conducted for 60-90 min at room temperature or 30° C.and terminated by rapid filtration. Specific binding is calculated bysubtracting non specific binding from total binding. The residualspecific binding at each ligand concentration is calculated andexpressed as a function of ligand concentration in order to constructsigmoidal concentration-response curves. The binding affinity of thecompounds is determined by calculating the equilibrium inhibitionconstant (K_(i)) from the equation K_(i)=InPt/1+[radioligand]/K_(d)where K_(d) is the equilibrium dissociation constant for theradioligand:receptor interaction and InPt is the inflection point of thedose-response curves.

Examples 1 to 23 were tested in the above binding assay for the EP4receptor and each demonstrated a Ki of less than 500 nM.

Prostanoid Receptor Agonist and Antagonist Assays

Whole cell second messenger assays measuring stimulation ofintracellular cAMP accumulation in HEK-293(ebna)-hEP4 cells areperformed to determine whether receptor ligands are agonists orantagonists. Cells are harvested and resuspended in HBSS containing 25mM HEPES, pH 7.4. Incubations contain 0.5 mM IBMX (phosphodiesteraseinhibitor, available from Biomol). Samples are incubated at 37° C. for10 min, the reaction is terminated and cAMP levels are then measured.Ligands are added in dimethylsulfoxide which is kept constant at 1%(v/v; agonists) or 2% (v/v; antagonists) in all incubations. Foragonists, second messenger responses are expressed as a function ofligand concentration and both EC₅₀ values and the maximum response ascompared to a PGE₂ standard are calculated. For antagonists, the abilityof a ligand to inhibit an agonist response is determined by carrying outdose-response curves in the presence of PGE₂ agonist at a concentrationcorresponding to its EC₇₀. IC₅₀ values are calculated as theconcentration of ligand required to inhibit 50% of the PGE₂-inducedactivity.

Rat Paw Edema Assay

The method is the same as described in Chan et al (J. Pharmacol. Exp.Ther. 274: 1531-1537, 1995).

Acute Inflammatory Hyperalgesia Induced by Carrageenan in Rats

The method is the same as described in Boyce et al (Neuropharmacology33: 1609-1611, 1994).

Adjuvant-Induced Arthritis in Rats

Female Lewis rats (body weight ˜146-170 g) are weighed, ear marked, andassigned to groups (a negative control group in which arthritis was notinduced, a vehicle control group, a positive control group administeredindomethacin at a total daily dose of 1 mg/kg and four groupsadministered with a test compound at total daily doses of 0.10-3.0mg/kg) such that the body weights were equivalent within each group. Sixgroups of 10 rats each are injected into a hind paw with 0.5 mg ofMycobacterium butyricum in 0.1 mL of light mineral oil (adjuvant), and anegative control group of 10 rats was not injected with adjuvant. Bodyweights, contralateral paw volumes (determined by mercury displacementplethysmography) and lateral radiographs (obtained under Ketamine andXylazine anesthesia) are determined before (day −1) and 21 daysfollowing adjuvant injection, and primary paw volumes are determinedbefore (day −1) and on days 4 and 21 following adjuvant injection. Therats are anesthetized with an intramuscular injection of 0.03-0.1 mL ofa combination of Ketamine (87 mg/kg) and Xylazine (13 mg/kg) forradiographs and injection of adjuvant. The radiographs are made of bothhind paws on day 0 and day 21 using the Faxitron (45 kVp, 30 seconds)and Kodak X-OMAT TL film, and are developed in an automatic processor.Radiographs are evaluated for changes in the soft and hard tissues by aninvestigator who was blinded to experimental treatment. The followingradiographic changes are graded numerically according to severity:increased soft issue volume (0-4), narrowing or widening of joint spaces(0-5) subchondral erosion (0-3), periosteal reaction (0-4), osteolysis(0-4) subluxation (0-3), and degenerative joint changes (0-3). Specificcriteria are used to establish the numerical grade of severity for eachradiographic change. The maximum possible score per foot was 26. A testcompound at total daily doses of 0.1, 0.3, 1, and 3 mg/kg/day,indomethacin at a total daily dose of 1 mg/kg/day, or vehicle (0.5%methocel in sterile water) are administered per os b.i.d. beginning postinjection of adjuvant and continuing for 21 days. The compounds areprepared weekly, refrigerated in the dark until used, and vortex mixedimmediately prior to administration.

The invention is further illustrated by the methods of synthesis andexamples that follow.

Method of Synthesis

In the above schemes, the designation Ar corresponds to Ar² in Formula Iand is optionally substituted as described herein.

EXAMPLE 14-[(1S)-1-({[1-(3-chlorobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicAcid-Potassium Salt

Step 1 1-(tert-butoxycarbonyl)indoline-7-carboxylic Acid

tert-butyl indoline-1-carboxylate (25 g, 114 mmol) and TMEDA (22.87 ml,151 mmol) were added to 567 ml ether. The solution was cooled to −78° C.and s-BuLi in c-hexane (1.2 eq, 1.4M) was added dropwise. The mixturewas stirred at this temperature for 1 hour. CO₂ gas was bubbled in themixture for 5 min and the bath was removed. After 10 min of stirring,the mixture was quenched with 1N HCl, warmed to RT and extracted 3× withEtOAc. The combined organic layers were washed with brine and dried overMgSO₄. Triturate with 1:1 ether/hexanes. ¹H NMR (500 MHz, DMSO-d₆): δ12.5 (bs, 1H), 7.35 (m, 2H), 7.05 (t, 1H), 4.00 (t, 2H), 3.00 (t, 2H),1.45 (s, 9H).

Step 2 tert-butyl7-[({(1S)-1-[4-(methoxycarbonyl)phenyl]ethyl}amino)carbonyl]indoline-1-carboxylate

1-(tert-butoxycarbonyl)indoline-7-carboxylic acid (0.5 g, 1.9 mmol),HATU (795 mg, 2.09 mmol) and(1S)-1-[4-(methoxycarbonyl)phenyl]ethanaminium chloride (511 mg, 2.85mmol) were added to acetonitrile (12.7 ml). The solution was cooled inan ice bath and DIPEA (993 ul, 5.7 mmol) was added. The ice bath wasremoved and the mixture stirred for 2 hours at RT. The solvent wasremoved and the crude mixture purified by flash chromatography on silicagel. ¹H NMR (500 MHz, DMSO-d₆): δ 8.40 (d, 1H), 7.90 (d, 2H), 7.55 (d,2H), 7.30 (d, 1H), 7.25 (d, 1H), 7.00 (t, 1H), 5.10 (m, 1H), 4.00 (m,2H), 3.85 (s, 3H), 3.05 (m, 2H), 1.45 (d, 3H), 1.40 (s, 9H).

Step 3 Methyl4-{(1S)-1-[(2,3-dihydro-1H-indol-7-ylcarbonyl)amino]ethyl}benzoate

tert-butyl7-[({(1S)-1-[4-(methoxycarbonyl)phenyl]ethyl}amino)carbonyl]indoline-1-carboxylate(510 mg, 1.2 mmol) was dissolved in CH₂Cl₂ (5 ml) and TFA (5 ml) wasadded, the solution was stirred for 1 hour. The solvent was removed.NaHCO₃ (sat.) was added and extracted 3× with EtOAc. The combinedorganic layers were washed with water and brine, then dried over MgSO₄.1H NMR (500 MHz, DMSO-d₆): δ 8.50 (d, 1H), 7.90 (d, 2H), 7.55 (m, 3H),7.10 (d, 1H), 6.50 (m, 2H), 5.15 (m, 1H), 3.85 (s, 3H), 3.50 (m, 2H),2.90 (m, 2H), 1.40 (d, 3H).

Step 4 Methyl4-[(1S)-1-({[1-(3-chlorobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoate

methyl4-{(1S)-1-[(2,3-dihydro-1H-indol-7-ylcarbonyl)amino]ethyl}benzoate (354mg, 1.09 mmol) was dissolved in ACN (5.5 ml), benzyl bromide (269 mg,1.31 mmol) and Hunig's base (0.38 ml, 2.18 mmol) were added. The mixturestirred at 70° C. for 2 hours. The solvent was removed. Purification onsilica gel. ¹H NMR (500 MHz, DMSO-d₆): δ 8.90 (d, 1H), 7.75 (d, 2H),7.40 (d, 2H), 7.25 (m, 3H), 7.15 (m, 2H), 7.05 (d, 1H), 6.65 (t, 1H),5.00 (m, 1H), 4.10 (m, 2H),), 3.85 (s, 3H), 3.20 (m, 2H), 2.90 (m, 2H),1.30 (d, 3H).

Step 54-[(1S)-1-({[1-(3-chlorobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicAcid-Potassium Salt

methyl4-[(1S)-1-({[1-(3-chlorobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoate(289 mg, 0.644 mmol) was dissolved in EtOH (3 ml). 2M KOH (0.416 ml,0.708 mmol) was added and the mixture stirred at 80° C. for 2 hours. Themixture was cooled and the solvents removed. ¹H NMR (500 MHz, DMSO-d₆):δ 8.85 (d, 1H), 7.65 (d, 2H), 7.40 (s, 1H), 7.30 (m, 2H), 7.15 (m, 4H),7.05 (d, 1H), 6.75 (t, 1H), 5.00 (m, 1H), 4.30 (dd, 2H), 3.20 (m, 2H),2.90 (t, 2H), 1.25 (d, 3H).

EXAMPLE 24-[(1S)-1-({[1-(4-trifluoromethyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicAcid-Potassium Salt

Step 14-[(1S)-1-({[1-(4-trifluoromethyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicAcid-Potassium Salt

Methyl4-{(1S)-1-[(2,3-dihydro-1H-indol-7-ylcarbonyl)amino]ethyl}benzoate (150mg, 0.462 mmol) was dissolved in ACN (1.9 ml), 4-(trifluoromethyl)benzylbromide (132 mg, 0.554 mmol) and Hunig's base (0.161 ml, 0.924 mmol)were added. The mixture stirred at 70° C. for 2 hours. The solvent wasremoved. Purification on silica gel. The resulting methyl ester (89 mg,0.184 mmol) was dissolved in EtOH (0.86 ml), 2M KOH (0.119 ml, 0.202mmol) was added and the mixture stirred at 80° C. for 2 hours. Themixture was cooled and the solvents removed. 1H NMR (500 MHz, DMSO-d₆):δ 8.75 (d, 1H), 7.70 (d, 2H), 7.65 (d, 2H), 7.55 (d, 2H), 7.15 (m, 3H),7.05 (d, 1H), 6.75 (t, 1H), 5.00 (m, 1H), 4.30 (dd, 2H), 3.30 (m, 2H),2.95 (t, 2H), 1.20 (d, 3H).

All compounds shown below, except Examples 18 and 21, were preparedaccording to scheme 1 and were prepared as their respective potassiumsalts. Examples 18 and 21 are readily made by one having ordinary skillin the art following the synthetic routes described herein with theappropriate modifications.

Example Structure Name m/z 1

4-[(1S)-1-({[1-(3-chlorobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicacid433.1(M + 1) 2

4-{(1S)-1-[({1-[4-(trifluoromethyl)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoicacid467.1(M + 1) 3

4-[(1S)-1-({[1-(3-cyanobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicacid423.8(M + 1) 4

4-[(1S)-1-({[1-(4-cyanobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicacid423.8(M − 1) 5

4-[(1S)-1-({[1-(3-chloro-4-iodobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicacid558.6(M + 1) 6

4-[(1S)-1-({[1-(4-iodobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicacid525.2(M + 1) 7

4-[(1S)-1-({[1-(3,5-dibromobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicacid556.8(M + 1) 8

4-{(1S)-1-[({1-[3-(aminocarbonyl)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoicacid442.0(M + 1) 9

4-[(1S)-1-({[1-(3,4-dichlorobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicacid467.0(M + 1) 10

4-{(1S)-1-[({1-[3-(trifluoromethyl)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoicacid467.1(M + 1) 11

4-[(1S)-1-({[1-(biphenyl-4-ylmethyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicacid475.3(M + 1) 12

4-[(1S)-1-({[1-(4-bromobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicacid479.1(M + 1) 13

4-{91S)-1-[({1-[4-(aminocarbonyl)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoicacid442.0(M + 1) 14

4-{(1S)-1-[({1-[4-(trifluoromethoxy)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoicacid483.0(M + 1) 15

4-[(1S)-1-({[1-(2,5-dichlorobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicacid467.0(M + 1) 16

4-[1-({[1-(3,4-dichlorobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)cyclopropyl]benzoicacid 480.8(M + 1) 17

4-[(1S)-1-({[1-(2-naphthylmethyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicacid449.0(M + 1) 18

1-(3,4-dichlorobenzyl)-N-{1-[4-(1H-tetrazol-5-yl)phenyl]cyclopropyl}indoline-7-carboxammide503.0(M + 1) 19

4-{(1S)-1-[({1-[2-bromo-4-(trifluoromethyl)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoicacid547.1(M + 1) 20

4-{(1S)-1-[({1-[4-(chloro)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoicacid435.0(M + 1) 21

N-{(1S)-1-[4-(1H-tetrazol-5-yl)phenyl]ethyl-1-[4-(trifluoromethyl)benzyl]indoline-7-carboxamide493.2(M + 1) 22

4-{(1S)-1-[({5-chloro-1-[4-(chloro)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoicacid503.1(M + 1) 23

4-{(1S)-1-[({1-[4-(trifluoromethoxy)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoicacid483.0(M + 1)

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein: X is —COOH ortetrazol-5-yl; each of A, B and C is independently selected from N, CHand C(R³), with the proviso that not more than one of A, B or C may beN; D is —C(R)₂— or —N(R)—, wherein each R is independently selected fromthe group consisting of: hydrogen, C₁₋₄alkyl, C₁₋₄fluoroalkyl,C₁₋₄alkoxy, C₁₋₄fluoroalkoxy and acetyl; Ar¹ and Ar² are independentlyselected from the group consisting of: C₃₋₆cycloalkyl, aryl, heteroaryland heterocyclyl, or a fused analog of C₃₋₆cycloalkyl, aryl, heteroaryland heterocyclyl, wherein Ar¹ is optionally substituted with one tothree R¹ groups and Ar² is optionally substituted with one to three R²groups; and each R¹, R² and R³ is independently selected from the groupconsisting of: halo, —CN, C₁₋₄alkyl, C₁₋₄fluoroalkyl, C₁₋₄alkoxy,C₁₋₄fluoroalkoxy, acetyl, aminocarbonyl and phenyl, R⁴ and R⁵ areselected from the group consisting of: hydrogen and C₁₋₄alkyl, or R⁴ andR⁵ may be joined together with the atom to which they are attached toform a C₃₋₆cycloalkyl group.
 2. The compound according to claim 1wherein R⁴ is methyl and R⁵ is hydrogen or R⁴ and R⁵ are joined togetherwith the atom to which they are attached to form cyclopropyl.
 3. Thecompound according to claim 1 wherein Ar¹ is phenyl, optionallysubstituted with one to three R¹ groups.
 4. The compound according toclaim 1 wherein Ar² is phenyl, optionally substituted with one to threeR² groups.
 5. The compound according to claim 1 wherein each of A, B andC is independently selected from CH and C(R³).
 6. The compound accordingto claim 1 wherein X is —COOH.
 7. The compound according to claim 1 ofFormula Ia

or a pharmaceutically acceptable salt thereof, wherein: R² is selectedfrom the group consisting of: halo, —CN, C₁₋₄alkyl, C₁₋₄fluoroalkyl,C₁₋₄alkoxy, C₁₋₄fluoroalkoxy, acetyl, aminocarbonyl and phenyl.
 8. Thecompound according to claim 7 wherein at least one R² group is present.9. A compound according to claim 1 selected from the following group:4-[(1S)-1-({[1-(3-chlorobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicacid;4-{(1S)-1-[({1-[4-(trifluoromethoxy)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoicacid;4-[(1S)-1-({[1-(3-cyanobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicacid;4-[(1S)-1-({[1-(4-cyanobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicacid;4-[(1S)-1-({[1-(3-chloro-4-iodobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicacid;4-[(1S)-1-({[1-(4-iodobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicacid;4-[(1S)-1-({[1-(3,5-dibromobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicacid;4-{(1S)-1-[({1-[3-(aminocarbonyl)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoicacid;4-[(1S)-1-({[1-(3,4-dichlorobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicacid;4-{(1S)-1-[({1-[3-(trifluoromethyl)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoicacid;4-[(1S)-1-({[1-(biphenyl-4-ylmethyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicacid;4-[(1S)-1-({[1-(4-bromobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicacid;4-{(1S)-1-[({1-[4-(aminocarbonyl)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoicacid;4-{(1S)-1-[({1-[4-(trifluoromethyl)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoicacid;4-[(1S)-1-({[1-(2,5-dichlorobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicacid;4-[1-({[1-(3,4-dichlorobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)cyclopropyl]benzoicacid;4-[(1S)-1-({[1-(2-naphthylmethyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoicacid;1-(3,4-dichlorobenzyl)-N-{1-[4-(1H-tetrazol-5-yl)phenyl]cyclopropyl}indoline-7-carboxamide;4-{(1S)-1-[({1-[2-bromo-4-(trifluoromethyl)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoicacid;4-{(1S)-1-[({1-[4-(chloro)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoicacid;N-{(1S)-1-[4-(1H-tetrazol-5-yl)phenyl]ethyl}-1-[4-(trifluoromethyl)benzyl]indoline-7-carboxamide;and4-{(1S)-1-[({5-chloro-1-[4-(chloro)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoicacid; or a pharmaceutically acceptable salt of any of theaforementioned.
 10. A pharmaceutical composition comprising a compoundaccording to claim 1 in admixture with one or more physiologicallyacceptable carriers or excipients.
 11. A compound according to claim 1or a pharmaceutically acceptable derivative thereof for use in human orveterinary medicine.